Grant: Project Grant

We are quite literally defined by our brain cells and their ability to communicate with each other. All of the memories and experiences that make us who we are rely on efficient communication between brain cells. When this communication fails, as is seen in Alzheimer disease (AD), our memories and our understanding of ourselves and the world around us begins to vanish. In the present grant proposal, we aim to better understand how brain cell communication begins to fail in AD. By using mice that express gene mutations linked to familial forms of AD, we have developed a novel technical approach that allows us to visualize an important chemical messenger at resolutions that were not possible just a few years ago. We show that this chemical, called glutamate, accumulates to toxic levels at specific areas that are only observable at the microscopic level. The areas exposed to toxic levels of glutamate are known as presynaptic terminals, and they are responsible for regulating the release of chemicals required for brain cell communication. Here, we will test the hypothesis that excess glutamate at the presynaptic terminal represents a very early pathological event in the AD brain that causes a variety of negative consequences on brain cell communication, ultimately resulting in the loss of brain connections. As the loss of brain connections is directly linked to cognitive decline in AD, we propose a therapeutic approach that can specifically reduce glutamate to control levels, with the expectation that it can help prevent the loss of connections and the cognitive decline known to occur in these AD mice. If successful, our data will identify a therapeutic avenue for the treatment of AD that is aimed primarily at preserving as many brain cell connections as possible.